1. Field of the Invention
This disclosure relates to the field of vitamin C, or ascorbic acid, compositions. This disclosure also relates to the field of treatments for striae, including but not exclusive to, striae gravidarum, striae atrophicae, striae distensae, and pubertal striae; i.e., stretch marks, and the fields of treatments for radiation dermatitis, rhytids, lentigoes, dyschromia, sun-damage hyperpigmentation, cellulite, purpura and scars, amongst other skin diseases and conditions.
2. Description of Related Art
Vitamin C, or ascorbic acid, is a water-soluble micronutrient; it is an essential nutrient for humans. The vital role of ascorbic acid in human physiology flows from the essential role that ascorbate (an ion of ascorbic acid) plays in a wide range of metabolic reactions. As a strong electron donor or reducing agent, vitamin C sequentially donates two electrons from the double bond between carbons two and three. With the loss of these electrons, vitamin C is oxidized and another compound is reduced. Accordingly, vitamin C is commonly known as an antioxidant.
In humans, vitamin C is an essential cofactor for eight (8) different enzymes. Three (3) of these enzymes participate in collagen hydroxylation. Collagen is a group of naturally occurring proteins which are found in the fibrous tissues of the human body such as tendons, ligaments and skin. Ascorbic acid has been found to be an essential cofactor in the hydroxylation of proline and lysine to form hydroxyproline and hydroxylysine, amino acids necessary for the function of collagen. In fact, some studies have demonstrated that ascorbic acid can stimulate collagen synthesis preferentially without affecting non-collagen protein synthesis. See Murad S., et al., Regulation of Collagen Synthesis by Ascorbic Acid, Proc. Natl. Acad. Sci., 78:2870 (1981).
The same properties that make vitamin C an excellent antioxidant (its electron donor propensities) render it difficult to create a stable vitamin C formulation, as it generally rapidly oxidizes upon exposure to air. Notoriously, in the presence of water, light, air and/or high temperatures, vitamin C is not stable, generally having a half life of minutes. In fact, at higher pHs ascorbic acid increasingly becomes more unstable. Thus, historically, it has been difficult to develop stable vitamin C compositions. While stabilized topical vitamin C compositions are known; e.g., See Kaplan, et al., A New Stabilized Ascorbic Acid Solution: Percutaneous Absorption and Effect on Relative Collagen Synthesis, Journal of Cutaneous Aging & Cosmetic Dermatology, 1:115 (1988/89) (disclosing a 5% solution of L-ascorbic acid in a hydroalcoholic vehicle), the stability of such compositions generally have been shown only up to about one (1) month. After that time, the formulation begins to rapidly oxidize and decompose. Thus, even the “stable” topical vitamin C formulations that are currently known to those of skill in the art have a minimal shelf life and efficacy period. Furthermore, typically, when these known ascorbic acid solutions are exposed to heat, rapid degradation of the ascorbic acid solution results. This instability and potential for rapid degradation of the prior topical vitamin C formulations generally results in a high cost of manufacturing, high cost of distribution, and issues associated with storage and availability to the end consumer.
In addition to issues of stability, there also has been uncertainty with regard to the ability of the currently utilized ascorbic acid compositions to deliver pharmacologic doses of ascorbic acid percutaneously (i.e., through the skin) If ascorbic acid is to effect the connective tissue of the skin, it must penetrate the stratum corneum (i.e., the outermost layer of the epidermis of the skin) and be available to the dermal fibroblasts (i.e., the cells of the skin that synthesize collagen). While penetration of the stratum corneum with topical vitamin C solutions for delivery to the dermis (i.e., the layer of skin between the epidermis and subcutaneous tissues) are known, these solutions either suffer from a low absorption rate over time (See Kaplan, et al., A New Stabilized Ascorbic Acid Solution: Percutaneous Absorption and Effect on Relative Collagen Synthesis, Journal of Cutaneous Aging & Cosmetic Dermatology, 1:115 (1988/89) (Absorption progressed linearly for 72 hours and with 12.4% absorption traversing the epidermal barrier)) or instability of the topical solution itself (See Pinnell, S. R., et al., Topical L-Ascorbic Acid: Percutaneous Absorption Studies, Dermatol. Surg., 27(2): 137-42 (2001) (showing that daily application of an L-ascorbic acid topical solution, with a pH of 3.5 or lower, resulted in saturating skin concentrations of L-ascorbic acid at more than 20 times the control values, for four days)).
This difficulty in the art with regard to the ability to deliver pharmacologic doses of ascorbic acid percutaneously has resulted in ascorbic acid formulations with four main problems. First, these formulations often lack a sufficient concentration of ascorbic acid to be effective. In order to achieve some minimal level of stability, these formulations have low concentrations of ascorbic acid. Second, these formulations are often in suspension rather than solution, making the formulation unavailable for percutaneous absorption since it is not in a dissolved state. Third, these formulations often incorporate ascorbic acid salts that, while being more stable, do not have the same pharmacological effect as ascorbic acid on the fibroblast for collagen synthesis and do not have the same percutaneous absorption characteristics. Fourth, the rapid degradation of the ascorbic acid prevents the ascorbic acid from reaching its target in the dermal layer of the skin in a stabilized form. Thus, it is unable to exert a physiologic effect on the fibroblasts.
A stable ascorbic acid composition which could be absorbed percutaneously would have application in a number of skin diseases and conditions which are associated with a decrease or disruption in collagen synthesis. Striae gravidarum is one such condition. Striae gravidarum, otherwise known as stretch marks, is a commonly known, but poorly understood, skin disconfiguring condition. Generally, stretch marks are characterized by a thinning of the connective tissue seronia to produce linear, atrophic-appearing skin. Stretch marks are a commonly recognized condition in both adolescent growth and pregnancy, among other situations.
Although the prevalence of stretch marks is high (among pregnant women it is reported to range between 50% and 90%) little is known about the aetiology and epidemiology of stretch marks. See Chang, Anne Lynn S, M.D., Risk Factors Associated with Striae Gravidarum, J. Am. Acad. Dermatol., December 2004, page 881. While the development of stretch marks is commonly thought to be caused by rapid weight gain, excessive endocrine activity, growth associated with adolescence or a degree of stretch in pregnancy, there are no scientific studies that verify any of these relationships. See Chang, Anne Lynn S, M.D., Risk Factors Associated with Striae Gravidarum, J. Am. Acad. Dermatol., December 2004, page 881. Further, other preliminary studies have suggested that family history, personal history, and race; i.e., genetic based factors, appear predictive of the development of striae gravidarum. See Chang, Anne Lynn S, M.D., Risk Factors Associated with Striae Gravidarum, J. Am. Acad. Dermatol., December 2004, page 883. While genetic factors, pregnancy weight gain, the growth and hormonal changes associated with adolescence and excessive adrencortical activity are the most frequent causative factors of stretch marks, the exact aetiology is not known.
In addition to the general confusion surrounding the aetiology and epidemiology of stretch marks, dissimilar descriptions of the histological changes in striae have created confusion to those of skill in the art. Some studies hypothesize (but have yet to observe) that striae are formed by an inflammatory reaction in a very early stage in striae formation that causes destruction of collagen and elastin. As in any other damage, this inflammation is followed by regeneration of new collagen and elastin, this time oriented in the direction of stress imposed by mechanical forces, as in rapid weight gain. See Zheng, P., et al., Anatomy of Straie, British Journal of Dermatology, 112, 185-193 (1985). The resultant damage has been shown, in some studies, to comprise variously a thin, flattened epidermis, thinning of the dermis, fraying and separation of collagen bundles with dilatation of blood vessels, and/or separation or total absence of elastic fibers. See Lee, K. S., Decreased Expression of Collagen and Fibronectin Genes in Straie Distensae Tissue, Clinical and Experimental Dermatology, 19:285-288 (1994).
Notably, despite its prevalence among pregnant women and adolescents, few preventative treatments are available for stretch marks. While there are a number of creams on the market that claim to remove stretch marks once they have developed, there is no reliable evidence to support such claims. Similarly, there are only two published randomized trials of preventive topical treatments and only one of these used a placebo control. From these studies it is not clear which, if any, particular ingredient is helpful in the prevention and/or treatment of stretch marks.
Taken together, the science surrounding the cause and treatment of stretch marks is in a state of bewilderment. Accordingly, there is a need in the art for an effective topical composition for the prevention and/or treatment of striae gravidarum, especially since currently there are no commercially available proven preventive products for stretch marks.
Radiation dermatitis is another skin condition which is associated with a decrease or disruption in collagen synthesis. Radiation dermatitis (also known as radiodermatitis) is an unintended skin reaction commonly experienced by patients receiving radiation therapy as part of their cancer treatment. This side effect, caused by radiation passing through the cells, is an unpleasant and painful condition for many cancer patients which, in some cases, may become so severe as to necessitate the interruption or cessation of radiation therapy. This, in turn, has been shown to decrease the efficacy of the radiation treatment and increase the likelihood of a cancer relapse.
Generally, radiation dermatitis manifests within a few weeks after the start of the radiotherapy. The onset of the condition varies in accordance with the radiation dose intensity, anatomic location of the radiation therapy, and the normal tissue sensitivity of individuals. This condition is experienced, to various degrees, by the majority of patients undergoing radiotherapy. While in most patients the dermatitis is mild to moderate, about 20-25% of patients experience severe reactions. Reddening of the skin, known as erythema, is an initial sign of skin dermatitis and may appear as early as the first treatment. Other symptoms also may include: epilation (i.e., hair loss), dry and wet desquamation (i.e., the shedding of the outer layers of the skin), decreased sweating, edema (i.e., swelling), ulcerations, bleeding, and skin cell death. Generally, the symptom progression has been shown to be linked with the total radiation dose, the dose per fraction, the overall treatment time, beam type and energy, and the surface area of the skin that is exposed to radiation. When the skin reaction is severe enough, it can interfere with the scheduling of the treatment regimen, which can adversely affect treatment outcomes by resulting in increased relapses of the malignancy and decreased patient survival rates.
Despite the prevalence of radiation dermatitis among individuals receiving radiation treatment, similar to striae gravidarum, there are few proven or known treatment options. While a variety of lotions, creams, and ointments have been recommended in the literature, there is a paucity of randomized trials with evidence to support the efficacy of these treatments. In fact, several trials evaluating topical agents have raised the question as to whether any product will actually prevent or promote the healing of radiation skin reactions. M. McQuestion, Evidence-Based Skin Care Management in Radiation Therapy, Seminars in Oncology Nursing, Vol 22, No. 3: 163-173 (2006).
Another skin condition associated with a disruption in collagen synthesis is the appearance of rhytids, commonly known as wrinkles Wrinkles are grooves in the skin. Wrinkles form when the skin looses its strength and elasticity, or the ability to stretch as the person ages. A number of factors are thought to be the cause of wrinkles, including: loss of the strength and elasticity of the skin with age; sun damage; repeated facial movements; and the natural effects of gravity, among others. Generally, individuals with the highest risk of developing wrinkles are fair-skinned people, people who have increased sun exposure and people who have a genetic predisposition to the development of wrinkles.
Currently, there is a wide variety of modalities known to those of skill in the art that are employed to treat rhytids. These include, but are not limited too, injectable fillers, injection of Clostridium Bitulinum (Botox®) or similar bacteria, implants, lifts, chemical peels, dermabrasion, laser resurfacing and/or the application of retinoic acid. These known and utilized treatments can be expensive and/or invasive options for the treatment/reduction of rhytids.
Lentigo, dyschromia (i.e., alteration in color to the skin or hair) and sun-damaged induced hyperpigmentation are additional skin conditions associated with disruptions in the production of collagen. Lentigo is a benign hyperplasia of melanocytes which spreads linearly. It generally shows up as a brown to black pigmented spot on the skin. Generally, the appearance of lentigos depends on varying factors such as an individual's history of sunlight exposure and genetic predisposition, amongst others. Similar to a lentigo, hyperpigmentation is the darkening of an area of the skin or nails caused by an increase in melanin. Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries. It is associated with a number of diseases, including, but not limited to, Addison's disease, Cushing's disease, and Celiac disease, amongst other diseases and conditions.
The appearance of cellulite is another skin condition associated with collagen synthesis. Cellulite is a topographical skin change which presents itself as a modification of the topography of the skin, generally evidenced by skin dimpling and nodularity. It occurs in many women (mainly in the pelvic region, lower limbs and abdomen) and is generally caused by the herniation of subcutaneous fat within fibrous connective tissue. Cellulite is not a serious medical condition, but many, for aesthetic reasons, are interested in treatment options for the prevention or reduction of its appearance. While numerous therapies for the treatment of cellulite are available on both a prescription and a non-prescription basis, the empirical evidence for the efficacy of these techniques is limited and questionable.
Sun induced or actinic purpura is also associated with disruptions in collagen synthesis. Purpura, which is caused by bleeding underneath the skin, manifests itself as the appearance of red or purple discolorations on the skin that do not blanch with the application of pressure to the skin. Purpura associated with sun damage are the result of chronic sun exposure which produces damage to the capillaries found in the skin, resulting in easy bruising.